Homer-mediated signaling and cocaine addiction

荷马介导的信号传导和可卡因成瘾

• 批准号: 8274891
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274891
• 关键词: Address; Animal Model; Behavior; Behavioral; Behavioral Genetics; Biochemical; Brain; Brain region; Cocaine; Cocaine Dependence; Cues; Data; Development; Dorsal; Drug Addiction; Drug Exposure; Family; Funding; Gene Delivery; Gene Targeting; Genetic; Genetic Polymorphism; Glutamates; Goals; Homer protein; Human; Immunoblotting; Immunologic Techniques; Individual; Injection of therapeutic agent; Intake; Knowledge; Laboratories; Lipase; Mediating; Microdialysis; Molecular; Neurobiology; Neuronal Plasticity; Neurotransmitters; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Phosphatidylinositols; Phospholipase; Phosphotransferases; Prefrontal Cortex; Process; Proteins; Regimen; Regulation; Relapse; Request for Proposals; Risk; Role; Scaffolding Protein; Screening procedure; Self Administration; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Site; Synapses; Testing; Time; Training; Treatment outcome; Viral; Virus; Withdrawal; abstracting; addiction; base; behavioral sensitization; cocaine exposure; craving; drug seeking behavior; in vivo; insight; mRNA Expression; neuroadaptation; neurochemistry; neurogenetics; neuropathology; new therapeutic target; phosphatidylinositol receptor; preference; prevent; protein expression; receptor; transmission process

Abstract/Project Summary Repeated cocaine exposure induces persistent, maladaptive changes in mesocorticolimbic glutamate transmission that are central to an addicted phenotype. Thus, likely molecular candidates contributing to the neuropathology of cocaine addiction are those regulating mesocorticolimbic glutamate transmission. Over the past 5 years, the Homer family of post-synaptic scaffolding proteins has emerged as a critical regulator of cocaine-induced changes in mesocorticolimbic glutamate and behavior that likely have relevance for the molecular underpinnings of hallmark features of addiction, such as relapse. A Homer1 polymorphism is significantly associated with cocaine addiction in humans and repeated cocaine administration, including excessive cocaine self-administration, alters mesocorticolimbic Homer mRNA and protein expression. Behavioral genetic studies indicated that a cocaine-induced increase in prefrontal cortex (PFC) Homer2 protein levels is sufficient, while a reduction in nucleus accumbens (NAC) Homer2 protein levels is both necessary and sufficient, for the expression of cocaine-seeking behavior, as assessed using place-preference paradigms. This project will extend these earlier data through a functional examination of the role for cocaine-induced changes in Homer2 expression within the dorsal and ventral PFC-NAC glutamate projections upon cocaine- paired cue-induced drug-seeking and associated changes in NAC glutamate during immediate, intermediate or protracted withdrawal from a period of excessive (40-60+ mg/kg/day) cocaine intake. Based on our previous immunoblotting and behavioral neurogenetics data, it is hypothesized that that excessive cocaine intake produces a time-dependent increase in PFC and decrease in NAC mGluR-Homer signaling pathways that underlie the intensification of drug-seeking during protracted withdrawal. Specific Aim 1 of this proposal will employ immunoblotting and in vivo microdialysis to test the specific hypothesis that the time- dependent intensification of cocaine-seeking during withdrawal from excessive cocaine self-administration is associated with time-dependent increases in PFC and decreases in NAC Homer-mediated signaling pathways within the dorsal mesocorticolimbic circuit, resulting in abnormal mesocorticolimbic glutamate release. Specific Aim 2 will employ site-directed viral-mediated gene delivery to examine the functional consequences of augmenting and preventing cocaine-induced changes in Homer2 within PFC-NAC projections for cocaine- paired cue-induced drug-seeking and NAC glutamate transmission. It is anticipated that the results obtained will greatly increase our understanding of the role for Homer2 in regulating excitatory glutamate transmission within the ventral and dorsal mesocorticolimbic subcircuits as it relates to time-dependent increases in relapse vulnerability. Such knowledge will point to cocaine-induced alterations in Homer2 regulation of both pre- and post-synaptic aspects of PFC-NAC glutamate transmission as critical neuroadaptations regulating the propensity to relapse during protracted withdrawal, which has high relevance for understanding addiction neuropathology and its treatment with glutamate-targeting pharmacotherapies.

摘要/项目摘要 反复接触可卡因会导致中皮质边缘谷氨酸发生持续的、适应不良的变化 传播是成瘾表型的核心。因此，可能的候选分子有助于 可卡因成瘾的神经病理学是调节中皮质边缘谷氨酸传输的神经病理学。超过 在过去 5 年里，突触后支架蛋白 Homer 家族已成为神经网络的关键调节因子。 可卡因引起的中皮质边缘谷氨酸和行为的变化可能与 成瘾标志性特征（例如复发）的分子基础。 Homer1 多态性是 与人类可卡因成瘾和重复使用可卡因显着相关，包括 过量的可卡因自我给药会改变中皮质边缘 Homer mRNA 和蛋白质的表达。 行为遗传学研究表明可卡因诱导前额皮质 (PFC) Homer2 蛋白增加 水平就足够了，而伏隔核 (NAC) Homer2 蛋白水平的降低既是必要的，也是 足以表达可卡因寻求行为，使用地点偏好范式进行评估。 该项目将通过对可卡因诱导作用的功能检查来扩展这些早期数据。 可卡因的背侧和腹侧 PFC-NAC 谷氨酸投射中 Homer2 表达的变化 配对线索诱导的药物寻求以及 NAC 谷氨酸在立即、中间或 从过量（40-60+毫克/公斤/天）可卡因摄入期间长期戒断。根据我们之前的 免疫印迹和行为神经遗传学数据，假设过量可卡因摄入 产生 PFC 的时间依赖性增加和 NAC mGluR-Homer 信号通路的减少 这是长期戒断期间寻求毒品加剧的基础。具体目标1 该提案将采用免疫印迹和体内微透析来测试特定的假设，即时间- 在戒除过量可卡因自我施用期间，可卡因寻求的依赖性强化是 与 PFC 的时间依赖性增加和 NAC Homer 介导的信号通路的减少相关 在背侧皮质边缘回路内，导致皮质边缘谷氨酸异常释放。具体的 目标 2 将采用定点病毒介导的基因传递来检查功能后果 在可卡因的 PFC-NAC 预测中增强和预防可卡因诱导的 Homer2 变化 配对线索诱导的药物寻找和 NAC 谷氨酸传输。预计得到的结果 将大大增加我们对 Homer2 在调节兴奋性谷氨酸传输中的作用的理解 在腹侧和背侧皮质边缘亚回路内，因为它与复发的时间依赖性增加有关 脆弱性。这些知识将指出可卡因引起的 Homer2 调节前和后的变化。 PFC-NAC 谷氨酸传递的突触后方面作为调节神经适应的关键 长期戒断期间复发的倾向，这与理解成瘾具有高度相关性 神经病理学及其谷氨酸靶向药物疗法的治疗。

项目成果

The motivational valence of methamphetamine relates inversely to subsequent methamphetamine self-administration in female C57BL/6J mice.

甲基苯丙胺的动机效价与雌性 C57BL/6J 小鼠随后自我施用甲基苯丙胺成反比。

• 发表时间: 2021
• 影响因子: 2.7
• 作者: Shab, Gabriella;Fultz, Elissa K;Page, Ariana;Coelho, Michal A;Brewin, Lindsey W;Stailey, Nicholas;Brown, Chelsea N;Bryant, Camron D;Kippin, Tod E;Szumlinski, Karen K
• 通讯作者: Szumlinski, Karen K

au Identification of a Deubiquitinating Enzyme as a Novel AGS 3-Interacting Protein

au 鉴定去泛素化酶作为新型 AGS 3 相互作用蛋白

• 发表时间: 2024-09-14
• 作者: Zhuojin Xu;Bin Xia;Q. Gong;Jeffrey K. Bailey;B. Groves;M. Radeke;S. Wood;K. Szumlinski;Dzwokai Ma
• 通讯作者: Dzwokai Ma

Incubation of cocaine-craving relates to glutamate over-flow within ventromedial prefrontal cortex.

可卡因渴望的酝酿与腹内侧前额叶皮层内谷氨酸的溢出有关。

• 发表时间: 2016-03
• 影响因子: 4.7
• 作者: Shin, Christina B;Serchia, Michela M;Shahin, John R;Ruppert;Kippin, Tod E;Szumlinski, Karen K
• 通讯作者: Szumlinski, Karen K

Imbalances in prefrontal cortex CC-Homer1 versus CC-Homer2 expression promote cocaine preference.

前额皮质 CC-Homer1 与 CC-Homer2 表达的不平衡会促进可卡因偏好。

• 发表时间: 2013-05-08
• 作者: Ary, Alexis W;Lominac, Kevin D;Wroten, Melissa G;Williams, Amy R;Campbell, Rianne R;Ben;von Jonquieres, Georg;Klugmann, Matthias;Szumlinski, Karen K
• 通讯作者: Szumlinski, Karen K

Deficits in ventromedial prefrontal cortex group 1 metabotropic glutamate receptor function mediate resistance to extinction during protracted withdrawal from an extensive history of cocaine self-administration.

腹内侧前额皮质第 1 组代谢型谷氨酸受体功能的缺陷介导了在长期戒断可卡因自我给药史期间对消退的抵抗力。

• 发表时间: 2013-01-09
• 作者: Ben;Sacramento, Arianne D;Miller, Bailey W;Webb, Sierra M;Wroten, Melissa G;Silva, Hannah E;Caruana, Amanda L;Gordon, Evan J;Ploense, Kyle L;Ditzhazy, Jennifer;Kippin, Tod E;Szumlinski, Karen K
• 通讯作者: Szumlinski, Karen K